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1.  Common genetic determinants of vitamin D insufficiency: a genome-wide association study 
Wang, Thomas J. | Zhang, Feng | Richards, J. Brent | Kestenbaum, Bryan | van Meurs, Joyce B. | Berry, Diane | Kiel, Douglas | Streeten, Elizabeth A. | Ohlsson, Claes | Koller, Daniel L. | Palotie, Leena | Cooper, Jason D. | O'Reilly, Paul F. | Houston, Denise K. | Glazer, Nicole L. | Vandenput, Liesbeth | Peacock, Munro | Shi, Julia | Rivadeneira, Fernando | McCarthy, Mark I. | Anneli, Pouta | de Boer, Ian H. | Mangino, Massimo | Kato, Bernet | Smyth, Deborah J. | Booth, Sarah L. | Jacques, Paul F. | Burke, Greg L. | Goodarzi, Mark | Cheung, Ching-Lung | Wolf, Myles | Rice, Kenneth | Goltzman, David | Hidiroglou, Nick | Ladouceur, Martin | Hui, Siu L. | Wareham, Nicholas J. | Hocking, Lynne J. | Hart, Deborah | Arden, Nigel K. | Cooper, Cyrus | Malik, Suneil | Fraser, William D. | Hartikainen, Anna-Liisa | Zhai, Guangju | Macdonald, Helen | Forouhi, Nita G. | Loos, Ruth J.F. | Reid, David M. | Hakim, Alan | Dennison, Elaine | Liu, Yongmei | Power, Chris | Stevens, Helen E. | Jaana, Laitinen | Vasan, Ramachandran S. | Soranzo, Nicole | Bojunga, Jörg | Psaty, Bruce M. | Lorentzon, Mattias | Foroud, Tatiana | Harris, Tamara B. | Hofman, Albert | Jansson, John-Olov | Cauley, Jane A. | Uitterlinden, Andre G. | Gibson, Quince | Järvelin, Marjo-Riitta | Karasik, David | Siscovick, David S. | Econs, Michael J. | Kritchevsky, Stephen B. | Florez, Jose C. | Todd, John A. | Dupuis, Josee | Hypponen, Elina | Spector, Timothy D.
Lancet  2010;376(9736):180-188.
Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.
We performed a genome-wide association study of 25-OH D among ∼30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L or <50 nmol/L.
Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 × 10-109 for rs2282679, in GC); 11q12 (P=2.1 × 10-27 for rs12785878, near DHCR7); 11p15 (P=3.3 × 10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (P=6.0 × 10-10 for rs6013897). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2- to 2.5-fold elevated odds of vitamin D insufficiency (P≤1 × 10-26).
Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1, CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency.
PMCID: PMC3086761  PMID: 20541252
2.  Relation of Lycopene Intake and Consumption of Tomato Products to Incident Cardiovascular Disease 
The British journal of nutrition  2013;110(3):545-551.
Evidence for cardioprotective effects of lycopene is inconsistent. Studies of circulating lycopene generally report inverse associations with cardiovascular disease (CVD) risk, but studies based on lycopene intake do not. The failure of the dietary studies to support the findings based on biomarkers may be due in part to misclassification of lycopene intakes. To address this potential misclassification, we used repeated measures of intake obtained over 10 years to characterize the relation between lycopene intake and incidence of CVD (n=314), coronary heart disease (CHD, n=171) and stroke (n=99) in the Framingham Offspring Study. Hazards ratios (HR) for incident outcomes were derived from Cox proportional hazards regression models using logarithmically transformed lycopene intake adjusted for CVD risk factors and correlates of lycopene intake. HRs were interpreted as the increased risk for a 2.7-fold difference in lycopene intake, a difference approximately equal to its inter-quartile range. Using an average of three intake measures with a 9 year follow-up, lycopene intake was inversely associated with CVD incidence (hazards ratio (HR): 0.83, 95% confidence interval (CI): 0.70-0.98). Using an average of two intake measures and 11 years of follow-up, lycopene intake was inversely associated with CHD incidence (HR: 0.74, 95% CI: 0.58-0.94). Lycopene intake was unrelated to stroke incidence. Our study of lycopene intake and CVD provides supporting evidence for an inverse association between lycopene and CVD risk but additional research is needed to determine if lycopene or other components of tomatoes, the major dietary source of lycopene, are responsible for the observed association.
PMCID: PMC3710301  PMID: 23317928
lycopene; cardiovascular disease; coronary heart disease; stroke
3.  Longitudinal association between dairy consumption and changes of body weight and waist circumference: the Framingham Heart Study 
Dairy foods are nutrient-dense and may be protective against long-term weight gain.
We aimed to examine the longitudinal association between dairy consumption and annualized changes in weight and waist circumference (WC) in adults.
Members of the Framingham Heart Study Offspring Cohort who participated in the 5th through 8th study examinations (1991–2008) were included in these analyses (3,440 participants with 11,683 observations). At each exam, dietary intake was assessed by a validated food frequency questionnaire, and weight and WC were assessed following standardized procedures. Repeated measures models were used for the longitudinal analyses by adjusting for time-varying or invariant covariates.
On average, participants gained weight and WC during follow-up. Dairy intake increased across exams. After adjusting for demographic and lifestyle factors (including diet quality), participants who consumed ≥3 servings/d of total dairy had 0.10 [±0.04] kg smaller annualized increment of weight (Ptrend=0.04) than those consuming <1 serving/d. Higher total dairy intake was also marginally associated with less WC gain (Ptrend=0.05). Similarly, participants who consumed ≥3 servings/wk of yogurt had a 0.10 [±0.04] kg and 0.13 [±0.05] cm smaller annualized increment of weight (Ptrend=0.03) and WC (Ptrend=0.008) than those consuming <1 serving/wk, respectively. Skim/low-fat milk, cheese, total high-fat or total low-fat dairy intake was not associated with long-term change of weight or WC.
Further longitudinal and interventional studies are warranted to confirm the beneficial role of increasing total dairy and yogurt intake, as part of a healthy and calorie-balanced dietary pattern, in the long-term prevention of gain in weight and WC.
PMCID: PMC3809320  PMID: 23736371
Dairy; Weight; Waist circumference; Longitudinal; Milk; Yogurt
4.  Magnesium Intake Is Inversely Associated With Coronary Artery Calcification 
JACC. Cardiovascular imaging  2013;7(1):59-69.
The aim of this study was to examine whether magnesium intake is associated with coronary artery calcification (CAC) and abdominal aortic calcification (AAC).
Animal and cell studies suggest that magnesium may prevent calcification within atherosclerotic plaques underlying cardiovascular disease. Little is known about the association of magnesium intake and atherosclerotic calcification in humans.
We examined cross-sectional associations of self-reported total (dietary and supplemental) magnesium intake estimated by food frequency questionnaire with CAC and AAC in participants of the Framingham Heart Study who were free of cardiovascular disease and underwent Multi-Detector Computed Tomography (MDCT) of the heart and abdomen (n = 2,695; age: 53 ± 11 years), using multivariate-adjusted Tobit regression. CAC and AAC were quantified using modified Agatston scores (AS). Models were adjusted for age, sex, body mass index, smoking status, systolic blood pressure, fasting insulin, total-to-high-density lipoprotein cholesterol ratio, use of hormone replacement therapy (women only), menopausal status (women only), treatment for hyperlipidemia, hypertension, cardiovascular disease prevention, or diabetes, as well as self-reported intake of calcium, vitamins D and K, saturated fat, fiber, alcohol, and energy. Secondary analyses included logistic regressions of CAC and AAC outcomes as cut-points (AS >0 and AS ≥90th percentile for age and sex), as well as sex-stratified analyses.
In fully adjusted models, a 50-mg/day increment in self-reported total magnesium intake was associated with 22% lower CAC (p < 0.001) and 12% lower AAC (p = 0.07). Consistent with these observations, the odds of having any CAC were 58% lower (p trend: <0.001) and any AAC were 34% lower (p trend: 0.01), in those with the highest compared to those with the lowest magnesium intake. Stronger inverse associations were observed in women than in men.
In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium's protective associations in stroke and fatal coronary heart disease.
PMCID: PMC3957229  PMID: 24290571
abdominal aortic calcification; computed tomography; coronary artery calcification; diet; Framingham Heart Study; magnesium
5.  Adherence to a vitamin D supplement intervention in urban schoolchildren 
Journal of the Academy of Nutrition and Dietetics  2013;114(1):10.1016/j.jand.2013.06.350.
Vitamin D supplementation is an important strategy for preventing low levels of serum 25OHD and improving bone health and consequent associated health risks, especially in children at risk of deficiency. Although vitamin D supplements are recommended, there is limited research on the factors that influence adherence to taking them. In a cross-sectional sample of 256 child (aged 9–15) and parent pairs in the Boston area during January-March 2012, ANCOVA was used to determine associations between health beliefs about vitamin D, parental vitamin D-containing supplement use, and the individual responsible for pill administration with supplement adherence measured by pill counts. Mean and median supplement pill count adherence over 3-months were 84% and 89%, respectively. Adherence was positively associated with parents’ use of vitamin D-containing supplements (7% higher, P=0.008) and with combined child and parent responsibility for administration of the supplement compared to child only (9% higher, P=0.03). Parents’ beliefs about vitamin D neither predictedtheir children’s beliefs nor positively influenced children’s adherence. Adherence was higher when parents took vitamin D-containing supplements and when parents and children shared responsibility for administering the supplement. Promoting child supplement use through parent involvement and role modeling may be a practical solution for dietitians who are aiming to improve vitamin D adherence in at-risk youth.
PMCID: PMC3867533  PMID: 23999277
Vitamin D; adherence; supplementation; children; parents
6.  Do Flavonoids Reduce Cardiovascular Disease Incidence or Mortality in US and European Populations? 
Nutrition reviews  2012;70(9):491-508.
Twenty publications from twelve prospective cohorts evaluated associations between flavonoid intakes and incidence or mortality from cardiovascular disease among adults in Europe and the United States (US). The most common outcome was coronary heart disease mortality, and four of eight cohort studies reported significant inverse associations for at least one flavonoid class (multivariate adjusted ptrend <.05). Three of seven cohorts reported that greater flavonoid intake was associated with lower risk of incident stroke. Comparisons were difficult because of variability in the flavonoid classes included, demographic characteristics of the populations, outcomes assessed, and length of follow up. The most common flavonoid classes examined were flavones and flavonols combined (11 studies). Only one study examined all seven flavonoid classes. The flavonol and flavone classes were most strongly associated with lower CHD mortality. Evidence for protection from other flavonoid classes and CVD outcomes was more limited. The hypothesis that flavonoid intakes are associated with lower CVD incidence and mortality requires further study.
PMCID: PMC4130174  PMID: 22946850
flavonoids; cardiovascular disease; coronary heart disease; stroke; prospective cohort studies; United States; Europe
7.  Confounding by Dietary Patterns of the Inverse Association Between Alcohol Consumption and Type 2 Diabetes Risk 
American Journal of Epidemiology  2009;170(1):37-45.
The ability to interpret epidemiologic observations is limited because of potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome the limitation. To examine confounding by dietary pattern as well as standard risk factors and selected nutrients, the authors modeled the longitudinal association between alcohol consumption and 7-year risk of type 2 diabetes mellitus in 2,879 healthy adults enrolled in the Framingham Offspring Study (1991–2001) by Cox proportional hazard models. After adjustment for standard risk factors, consumers of ≥9.0 drinks/week had a significantly lower risk of type 2 diabetes mellitus compared with abstainers (hazard ratio = 0.47, 95% confidence interval (CI): 0.27, 0.81). Adjustment for selected nutrients had little effect on the hazard ratio, whereas adjustment for dietary pattern variables by factor analysis significantly shifted the hazard ratio away from null (hazard ratio = 0.33, 95% CI: 0.17, 0.64) by 40.0% (95% CI: 16.8, 57.0; P = 0.002). Dietary pattern variables by partial least squares showed similar results. Therefore, the observed inverse association, consistent with past studies, was confounded by dietary patterns, and this confounding was not captured by individual nutrient adjustment. The data suggest that alcohol intake, not dietary patterns associated with alcohol intake, is responsible for the observed inverse association with type 2 diabetes mellitus risk.
PMCID: PMC2733040  PMID: 19429876
alcohol drinking; bias (epidemiology); confounding factors (epidemiology); diabetes mellitus, type 2; diet; factor analysis, statistical; least-squares analysis; proportional hazards models
8.  Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts 
American Journal of Epidemiology  2012;177(2):103-115.
Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = −0.004 mmol/L, 95% confidence interval: −0.005, −0.003) and FI (β = −0.008 ln-pmol/L, 95% confidence interval: −0.009, −0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.
PMCID: PMC3707424  PMID: 23255780
diabetes; dietary pattern; gene-environment interaction; glucose; insulin
9.  Yogurt consumption is associated with better diet quality and metabolic profile in American men and women 
The evidence-based Dietary Guidelines for Americans recommends increasing the intake of fat-free or low-fat milk and milk products. However, yogurt, a nutrient-dense milk product, has been understudied. This cross-sectional study examined whether yogurt consumption was associated with better diet quality and metabolic profile among adults (n = 6526) participating in the Framingham Heart Study Offspring (1998-2001) and Third Generation (2002-2005) cohorts. A validated food frequency questionnaire was used to assess dietary intake, and the Dietary Guidelines Adherence Index (DGAI) was used to measure overall diet quality. Standardized clinical examinations and laboratory tests were conducted. Generalized estimating equations examined the associations of yogurt consumption with diet quality and levels of metabolic factors. Approximately 64% of women (vs 41% of men) were yogurt consumers (ie, consumed >0 servings/week). Yogurt consumers had a higher DGAI score (ie, better diet quality) than nonconsumers. Adjusted for demographic and lifestyle factors and DGAI, yogurt consumers, compared with nonconsumers, had higher potassium intakes (difference, 0.12 g/d) and were 47%, 55%, 48%, 38%, and 34% less likely to have inadequate intakes (based on Dietary Reference Intake) of vitamins B2 and B12, calcium, magnesium, and zinc, respectively (all P ≤ .001). In addition, yogurt consumption was associated with lower levels of circulating triglycerides, glucose, and lower systolic blood pressure and insulin resistance (all P < .05). Yogurt is a good source of several micronutrients and may help to improve diet quality and maintain metabolic well-being as part of a healthy, energy-balanced dietary pattern.
PMCID: PMC3606818  PMID: 23351406
Yogurt; Milk; Diet; Nutrition status; Metabolic profile; Human
10.  Predicted 25-hydroxyvitamin D Score and Change in Fasting Plasma Glucose in the Framingham Offspring Study 
Data on the association between vitamin D status and actual change in glycemic measures are limited. We examined the prospective association between a predicted 25-hydroxyvitamin D (25(OH)D) score and change in fasting plasma glucose concentration over a mean follow-up of 7 years, in 2,571 men and women (mean age 54 yrs) without diabetes in the Framingham Offspring Study cohort. After adjustment for age, sex, BMI and fasting plasma glucose at baseline, higher predicted 25(OH)D score at baseline was associated with a smaller 7-year increase in fasting plasma glucose concentrations (0.23 mmol/l versus 0.35 mmol/l for highest vs. lowest tertile of 25(OH)D score respectively, P-trend=0.007). Vitamin D status may be an important determinant for change in fasting plasma glucose concentration among middle-aged and older adults without diabetes.
PMCID: PMC3796766  PMID: 22009071
11.  Cross-sectional association of dietary patterns with insulin resistance phenotypes among adults without diabetes in the Framingham Offspring Study 
The British journal of nutrition  2009;102(4):576-583.
Cluster analysis is a valuable tool for exploring the health consequences of consuming different dietary patterns. We used this approach to examine the cross-sectional relationship between dietary patterns and insulin resistance phenotypes, including waist circumference, body mass index (BMI), fasting insulin, 2-h post-challenge insulin, insulin sensitivity index (ISI0,120), HDL cholesterol, triacylglycerol and blood pressure, using data from the fifth examination cycle of the Framingham Offspring Study. Among 2,875 participants without diabetes, we identified four dietary patterns based on the predominant sources of energy: “Fruits, Reduced Fat Dairy and Whole Grains”, “Refined Grains and Sweets”, “Beer”, and “Soda”. After adjusting for multiple comparisons and potential confounders, compared with the “Fruits, Reduced Fat Dairy and Whole Grains” pattern, the “Refined Grains and Sweets” pattern had significantly higher mean waist circumference (92.4 versus 90.5 cm, P=0.008) and BMI (27.3 versus 26.6 kg/m2, P=0.02); the “Soda” pattern had significantly higher mean fasting insulin concentration (31.3 versus 28.0 μU/ml, P≤0.001); the “Beer” pattern had significantly higher mean HDL cholesterol concentration (1.46 versus 1.31 mmol/l, P<0.001). No associations were observed between dietary patterns and ISI0,120, triacylglycerol, and systolic or diastolic blood pressure. Our findings suggest that consumption of a diet rich in fruits, vegetables, whole grains and reduced fat dairy protects against insulin resistance phenotypes and displacing these healthy choices with refined grains, high fat dairy, sweet baked foods, candy and sugar sweetened soda promotes insulin resistant phenotypes.
PMCID: PMC3785063  PMID: 19216828
Dietary patterns; cluster analysis; insulin resistance phenotypes; Framingham Offspring Study
12.  Circulating folic acid in plasma: relation to folic acid fortification 
The implementation of folic acid fortification in the United States has resulted in unprecedented amounts of this synthetic form of folate in the American diet. Folic acid in circulation may be a useful measure of physiologic exposure to synthetic folic acid, and there is a potential for elevated concentrations after fortification and the possibility of adverse effects.
We assessed the effect of folic acid fortification on circulating concentrations of folic acid and 5-methyltetrahydrofolate in the Framingham Offspring Cohort.
This is a cross-sectional study that used plasma samples from fasting subjects before and after fortification. Samples were measured for folate distribution with the use of an affinity-HPLC method with electrochemical detection.
Among nonsupplement users, the median concentration of folic acid in plasma increased from 0.25 to 0.50 nmol/L (P < 0.001) after fortification, and among supplement users the median increased from 0.54 to 0.68 nmol/L (P = 0.001). Among nonsupplement users, the prevalence of high circulating folic acid (≥85th percentile) increased from 9.4% to 19.1% (P = 0.002) after fortification. Among supplement users, the prevalence of high circulating folic acid increased from 15.9% to 24.3% (P = 0.02). Folic acid intake and total plasma folate were positively and significantly related to high circulating folic acid after adjustment for potential confounding factors (P for trend < 0.001).
Folic acid fortification has resulted in increased exposure to circulating folic acid. The biochemical and physiologic consequences of this are unknown, but these findings highlight the need to understand the effects of chronic exposure to circulating folic acid.
PMCID: PMC3763811  PMID: 18779294
13.  Vitamin B-12 and Folate Status in Relation to Decline in Scores on the Mini-Mental State Examination in the Framingham Heart Study 
Biochemical evidence of low vitamin B-12 status is common in seniors, but its clinical relevance is unclear. Vitamin B-12 deficiency can result in rapid, irreversible cognitive decline – a phenomenon that has been linked to high folate status. Our objective was to investigate the cognitive significance of low to low-normal plasma vitamin B-12 concentrations. Secondarily, we sought to shed light on the role that folate status plays in the association between vitamin B-12 status and cognitive decline.
We evaluated associations between plasma vitamin B-12 and folate and 8-year cognitive decline. We also assessed interactions between vitamin B-12 status and both folate status and supplemental folate use in relation to cognitive decline.
The Framingham Heart Study -- a prospective epidemiologic study
Five hundred forty-nine community-dwelling seniors (mean age 74.8±4.6 years).
Mini-Mental State Examination (MMSE), plasma folate, vitamin B-12, methylmalonic acid, homocysteine, demographic factors, and body mass index.
MMSE scores declined by 0.24 points/year over the 8-year follow-up period. Decline was significantly accelerated among cohort members in the bottom two plasma vitamin B-12 quintile categories, and no apparent cognitive advantage was associated with plasma vitamin B-12 from 187–256.8 pmol/L versus <186 pmol/L. Among cohort members with plasma vitamin B-12<258 pmol/L, having a plasma folate concentration>20.2 nmol/L was associated with an approximate 1-point/year decline, as was use of supplemental folate.
Plasma vitamin B-12 from 187–256.8 pmol/L predicts cognitive decline. High plasma folate and supplemental folate use identify subgroups in this vitamin B-12 range and below who are prone to especially rapid cognitive decline.
PMCID: PMC3419282  PMID: 22788704
aged; cognition/*physiology; folic acid/blood; humans; methylmalonic acid/blood; vitamin B 12/*blood
14.  Higher Dietary Flavonol Intake Is Associated with Lower Incidence of Type 2 Diabetes12 
The Journal of Nutrition  2013;143(9):1474-1480.
Substantial experimental evidence suggests that several flavonoid classes are involved in glucose metabolism, but few clinical or epidemiologic studies exist that provide supporting human evidence for this relationship. The objective of this study was to determine if habitual intakes of specific flavonoid classes are related to incidence of type 2 diabetes (T2D). We followed 2915 members of the Framingham Offspring cohort who were free of T2D at baseline from 1991 to 2008. Diabetes was defined by either elevated fasting glucose (≥7.0 mmol/L) or initiation of hypoglycemic medication during follow-up. Dietary intakes of 6 flavonoid classes and total flavonoids were assessed using a validated, semiquantitative food frequency questionnaire. We observed 308 incident cases of T2D during a mean follow-up period of 11.9 y (range 2.5–16.8 y). After multivariable adjusted, time-dependent analyses, which accounted for long-term flavonoid intake during follow-up, each 2.5-fold increase in flavonol intake was associated with a 26% lower incidence of T2D [HR = 0.74 (95% CI: 0.61, 0.90); P-trend = 0.003] and each 2.5-fold increase in flavan-3-ol intake was marginally associated with an 11% lower incidence of T2D [HR = 0.89 (95% CI: 0.80, 1.00); P-trend = 0.06]. No other associations between flavonoid classes and risk of T2D were observed. Our observations support previous experimental evidence of a possible beneficial relationship between increased flavonol intake and risk of T2D.
PMCID: PMC3743276  PMID: 23902957
15.  Total Zinc Intake May Modify the Glucose-Raising Effect of a Zinc Transporter (SLC30A8) Variant 
Diabetes  2011;60(9):2407-2416.
Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.
We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.
We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: −0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: −0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.
Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.
PMCID: PMC3161318  PMID: 21810599
16.  Vitamin D Status is Not Related to Development of Atrial Fibrillation in the Community 
American heart journal  2011;162(3):538-541.
Atrial fibrillation (AF) is common and is an important cause of cardiovascular morbidity and mortality. Vitamin D is an emerging risk factor in cardiovascular disease, and vitamin D status is modifiable. Thus, we sought to investigate whether vitamin D status predisposed to the development of AF in a community-based sample.
We evaluated the relation between vitamin D status and development of AF in 2,930 participants of the Framingham Heart Study, Massachusetts, United States, without prevalent AF. The mean age was 65±11 years and 56% were women. Vitamin D status was assessed by measuring 25-hydroxyvitamin D (25[OH]D) concentrations. Multivariable Cox regression models were adjusted for AF risk factors and season.
During a mean follow up of 9.9 years, 425 participants (15%) developed AF. In Cox proportional hazards models, 25(OH)D was not associated with development of AF, with a multivariable-adjusted hazard ratio of 0.99 per SD increment in 25(OH)D levels (95% confidence interval [CI], 0.88 to 1.10; p=0.81). Also, no relation was found in models including 25(OH)D as a dichotomous variable (above and below the cohort-specific 20th percentile; p=0.59).
In our community-based sample, vitamin D status was not related to incident AF. Our data suggest that vitamin D deficiency does not promote the development of AF in the ambulatory setting.
PMCID: PMC3170821  PMID: 21884873
Atrial fibrillation; vitamin D; risk factors; biomarker
17.  Higher Aldosterone and lower N-Terminal proatrial natriuretic peptide as biomarkers of salt sensitivity in the community 
Salt sensitivity, a trait characterized by a pressor blood pressure (BP) response to increased dietary salt intake, has been associated with higher rates of cardiovascular target organ damage and cardiovascular disease events. Recent experimental studies have highlighted the potential role of the natriuretic peptides and aldosterone in mediating salt sensitivity.
Methods and Results:
We evaluated 1575 non-hypertensive Framingham Offspring cohort participants (mean age 55±9 years, 58% women) who underwent routine measurements of circulating aldosterone and N-terminal proatrial natriuretic peptide (NT-ANP) and assessment of dietary sodium intake. Participants were categorized as potentially ‘salt-sensitive’ if their serum aldosterone was >sex-specific median but plasma NT-ANP was ≤sex-specific median value. Dietary sodium intake was categorized as lower versus higher (dichotomized at the sex-specific median). We used multivariable linear regression to relate presence of salt sensitivity (as defined above) to longitudinal changes (Δ) in systolic and diastolic BP on follow-up (median 4 years). Participants who were ‘salt-sensitive’ (N=437) experienced significantly greater increases in BP (Δ systolic, +4.4 and +2.3 mmHg; Δ diastolic, +1.9 and −0.3 mmHg; on a higher versus lower sodium diet, respectively) as compared to the other participants (Δ systolic, +2.8 and +1.0 mmHg; Δ diastolic, +0.5 and −0.2 mmHg; on higher versus lower sodium diet, respectively; p=0.033 and p=0.0127 for differences between groups in Δ systolic and Δ diastolic BP, respectively).
Our observational data suggest that higher circulating aldosterone and lower NT-ANP concentrations may be markers of salt sensitivity in the community. Additional studies are warranted to confirm these observations.
PMCID: PMC3179529  PMID: 21450637
salt sensitivity; aldosterone; N-terminal proatrial natriuretic peptide; ANP
18.  Social network concordance in food choice among spouses, friends, and siblings 
American Journal of Public Health  2011;101(11):2170-2177.
We investigated whether eating behaviors were concordant among diverse sets of social ties.
We analyzed the socio-economic and demographic distribution of eating among 3,418 members of the Framingham Heart Study observed between 1991 and 2001. A data classification procedure simplified choices into seven non-overlapping patterns; these patterns were matched with information on social network ties. Correlation analysis examined eating associations between four types of peers (spouses, friends, brothers, sisters). Longitudinal multiple logistic regression was used to evaluate evidence for peer influences on eating.
Of all peer types, spouses showed strongest concordances in eating patterns over time after adjusting for social contextual factors. Across all peers, the eating pattern most likely to be shared by socially connected individuals is “alcohol and snacks.” Models estimating one’s current eating pattern based on a peer’s prior eating provide supportive evidence of a social influence process.
Certain eating patterns may be socially transmissible across different kinds of relationships. These findings represent an important step in specifying the relevant social environment in the study of health behaviors to include eating.
PMCID: PMC3222397  PMID: 21940920
19.  Segment-specific association between plasma homocysteine and carotid artery intima-media thickness in the Framingham Heart Study 
Higher plasma total homocysteine (tHcy) is an established risk factor for cardiovascular disease. The relation between tHcy and carotid artery intima-media thickness (IMT) at the internal carotid artery (ICA)/bulb-IMT and common carotid artery (CCA)-IMT has not been systematically examined. Since the ICA/bulb segment is more prone to plaque formation than the CCA segment, differential associations with tHcy at these sites might suggest mechanisms of tHcy action.
We examined the cross-sectional segment-specific relations of tHcy to ICA/bulb-IMT and CCA-IMT in 2,499 participants from the Framingham Offspring Study, free of cardiovascular disease.
In multivariable linear regression analysis, ICA/bulb-IMT was significantly higher in the fourth tHcy quartile category compared to the other quartile categories, in both the age- and sex-adjusted and in the multivariable-adjusted model (P for trend <0.0001 and <0.01, respectively). We observed a significant age by tHcy interaction for ICA/bulb-IMT (P=0.03) and therefore stratified the analyses by median age (58 years). There was a significant positive trend between tHcy and ICA/bulb-IMT in individuals 58 years of age or older (P-trend <0.01), but not in the younger individuals (P-trend=0.24). For CCA-IMT, no significant trends were observed in any of the analyses.
The segment-specific association between elevated tHcy levels and ICA/bulb-IMT suggests an association between tHcy and plaque formation.
PMCID: PMC3011043  PMID: 20580253
carotid artery; intima-media thickness; homocysteine; atherosclerosis; Framingham Offspring Study
20.  Relations of Biomarkers of Distinct Pathophysiological Pathways and Atrial Fibrillation Incidence in the Community 
Circulation  2010;121(2):200-207.
Biomarkers of multiple pathophysiological pathways have been related to incident atrial fibrillation (AF), but their predictive ability remains controversial.
Methods and Results
In 3120 Framingham cohort participants (mean age 58.4±9.7, 54% women), we related 10 biomarkers representing inflammation (C-reactive protein [CRP], fibrinogen), neurohormonal activation (B-type natriuretic peptide [BNP], N-terminal pro-atrial natriuretic peptide), oxidative stress (homocysteine), renin-angiotensin-aldosterone system (renin, aldosterone), thrombosis and endothelial function (D-dimer, plasminogen-activator inhibitor 1 [PAI-1]), and microvascular damage (urine albumin excretion, n=2673) with incident AF (n=209, 40% women) over a median follow-up of 9.7 years (range 0.05–12.8 years).
In multivariable-adjusted analyses, the biomarker panel was associated with incident AF (P<0.0001). In stepwise selection models (P<0.01 for entry and retention), log-transformed BNP, hazard ratio [HR] per standard deviation 1.62 (95% confidence interval [CI] 1.41–1.85, P<0.0001), and CRP, HR 1.25 (95% CI 1.07–1.45, P=0.004), were chosen.
The addition of BNP to variables recently combined in a risk score for AF increased the C-statistic from 0.78 (95%CI 0.75–0.81 to 0.80 (95% CI 0.78–0.83), and showed an integrated discrimination improvement of 0.03 (95% CI 0.02–0.04, P<0.0001) with 34.9% relative improvement in reclassification analysis. The combined analysis of BNP and CRP did not appreciably improve risk prediction over the model incorporating BNP in addition to the risk factors.
BNP is a predictor of incident AF and improves risk stratification based on well-established clinical risk factors. Whether knowledge of BNP concentrations may be used to target individuals at risk of AF for more intensive monitoring or primary prevention needs further investigation.
PMCID: PMC3224826  PMID: 20048208
atrial fibrillation; biomarkers; epidemiology; cohort; risk assessment
21.  A Multimarker Approach for Prediction of Heart Failure Incidence in the Community 
Circulation  2010;122(17):1700-1706.
Several biological pathways are activated in ventricular remodeling and in overt heart failure (HF). There are no data, however, on the incremental utility of a parsimonious set of biomarkers (reflecting pathways implicated in HF) for predicting HF risk in the community.
Methods and Results
We related a multi-biomarker panel to the incidence of a first HF event in 2754 Framingham Heart Study participants (mean age 58 years; 54% women), who were free of HF and underwent routine assays for 6 biomarkers (c-reactive protein, plasminogen activator inhibitor-1, homocysteine, aldosterone-to-renin ratio, b-type natriuretic peptide [BNP] and urinary albumin-to-creatinine ratio [UACR]). We estimated model c-statistic, calibration and net reclassification improvement (NRI) to assess the incremental predictive usefulness of biomarkers. We also related biomarkers to incidence of non-ischemic HF in participants without prevalent coronary heart disease.
On follow-up (mean 9.4 years), 95 first HF events occurred (54 in men). In multivariable-adjusted models, the biomarker panel was significantly related to HF risk (p=0.00005). Upon backwards elimination, BNP and UACR emerged as key biomarkers predicting HF risk: hazards ratio (HR; confidence interval [CI]) per standard deviation increment in log-marker were 1.52 (1.24-1.87) and 1.35 (1.11-1.66), respectively. BNP and UACR significantly improved the model c-statistic (CI) from 0.84 (0.80-0.88) in standard models to 0.86 (0.83-0.90), enhanced risk reclassification (NRI = 0.13; p=0.002), and were also independently associated with non-ischemic HF risk.
Using a multimarker strategy, we identified BNP and UACR as key risk factors for new-onset HF with incremental predictive utility over standard risk factors.
PMCID: PMC2993157  PMID: 20937976
Biomarkers; heart failure; risk; prediction
22.  Vitamin K and Vitamin D Status: Associations with Inflammatory Markers in the Framingham Offspring Study 
American journal of epidemiology  2007;167(3):313-320.
In vitro data suggest protective roles for vitamins K and D in inflammation. To examine associations between vitamins K and D and inflammation in vivo, we used multiple linear regression analyses, adjusted for age, sex, body mass index, triglyceride concentrations, use of aspirin, lipid lowering and hormone replacement medications, season, and menopausal status. Participants were from the Framingham Offspring Study (n=1381; mean age 59 years; 52% women). Vitamin K status, measured by plasma phylloquinone and phylloquinone intake, was inversely associated with circulating inflammatory markers as a group, and with several individual inflammatory biomarkers (p< 0.01). Percent undercarboxylated osteocalcin, a functional measure of vitamin K status, was not associated with overall inflammation, but was associated with C-reactive protein (p<0.01). Although plasma 25-hydroxyvitamin D was inversely associated with urinary isoprostanes, an oxidative stress indicator (p<0.01), overall associations between vitamin D status and inflammation were inconsistent. The observation that high vitamin K status was associated with lower concentrations of inflammatory markers suggests that a protective role for vitamin K in inflammation merits further investigation.
PMCID: PMC3151653  PMID: 18006902
inflammation; vitamin K; vitamin D; epidemiology
23.  Biomarkers of folate status in NHANES: a roundtable summary123456 
A roundtable to discuss the measurement of folate status biomarkers in NHANES took place in July 2010. NHANES has measured serum folate since 1974 and red blood cell (RBC) folate since 1978 with the use of several different measurement procedures. Data on serum 5-methyltetrahydrofolate (5MTHF) and folic acid (FA) concentrations in persons aged ≥60 y are available in NHANES 1999–2002. The roundtable reviewed data that showed that folate concentrations from the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA; used in NHANES 1991–1994 and NHANES 1999–2006) were, on average, 29% lower for serum and 45% lower for RBC than were those from the microbiological assay (MA), which was used in NHANES 2007–2010. Roundtable experts agreed that these differences required a data adjustment for time-trend analyses. The roundtable reviewed the possible use of an isotope-dilution liquid chromatography–tandem mass spectrometry (LC-MS/MS) measurement procedure for future NHANES and agreed that the close agreement between the MA and LC-MS/MS results for serum folate supported conversion to the LC-MS/MS procedure. However, for RBC folate, the MA gave 25% higher concentrations than did the LC-MS/MS procedure. The roundtable agreed that the use of the LC-MS/MS procedure to measure RBC folate is premature at this time. The roundtable reviewed the reference materials available or under development at the National Institute of Standards and Technology and recognized the challenges related to, and the scientific need for, these materials. They noted the need for a commutability study for the available reference materials for serum 5MTHF and FA.
PMCID: PMC3127517  PMID: 21593502
24.  Biomarkers of vitamin B-12 status in NHANES: a roundtable summary123456 
A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B-12–related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES—serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy)—and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. The roundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12–related biomarkers. They agreed that problems with sensitivity and specificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA.
PMCID: PMC3127527  PMID: 21593512
25.  Metabolite Profiles and the Risk of Developing Diabetes 
Nature medicine  2011;17(4):448-453.
Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines, and other polar metabolites were profiled in baseline specimens using liquid chromatography-tandem mass spectrometry. Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly-significant associations with future diabetes: isoleucine, leucine, valine, tyrosine, and phenylalanine. A combination of three amino acids predicted future diabetes (>5-fold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential importance of amino acid metabolism early in the pathogenesis of diabetes, and suggest that amino acid profiles could aid in diabetes risk assessment.
PMCID: PMC3126616  PMID: 21423183

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